Michaelis U Ruth, Fleming Ingrid
Vascular Signalling Group, Institut für Kardiovaskuläre Physiologie, Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
Pharmacol Ther. 2006 Sep;111(3):584-95. doi: 10.1016/j.pharmthera.2005.11.003. Epub 2005 Dec 27.
Epoxyeicosatrienoic acids (EETs) are generated from arachidonic acid by cytochrome P450 (CYP) epoxygenases. The expression of CYP epoxygenases in endothelial cells is determined by a number of physical (fluid shear stress and cyclic stretch) and pharmacological stimuli as well as by hypoxia. The activation of CYP epoxygenases in endothelial cells is an important step in the nitric oxide and prostacyclin (PGI2)-independent vasodilatation of several vascular beds and EETs have been identified as endothelium-derived hyperpolarizing factors (EDHFs). However, in addition to regulating vascular tone, EETs modulate several signaling cascades and affect cell proliferation, cell migration, and angiogenesis. Signaling molecules modulated by EETs include tyrosine kinases and phosphatases, mitogen-activated protein kinases, protein kinase A (PKA), cyclooxygenase (COX)-2, and several transcription factors. This review summarizes the role of CYP-derived EETs in cell signaling and focuses particularly on their role as intracellular amplifiers of endothelial cell hyperpolarization as well as in cell proliferation and angiogenesis. The angiogenic properties of CYP epoxygenases and CYP-derived EETs implicate that these enzymes may well be accessible targets for anti-angiogenic as well as angiogenic therapies.
环氧二十碳三烯酸（EETs）由细胞色素P450（CYP）环氧化酶催化花生四烯酸生成。CYP环氧化酶在内皮细胞中的表达受多种物理因素（流体剪切力和周期性拉伸）、药理刺激以及缺氧的影响。内皮细胞中CYP环氧化酶的激活是多个血管床中不依赖一氧化氮和前列环素（PGI2）的血管舒张的重要步骤，且EETs已被确定为内皮源性超极化因子（EDHFs）。然而，除了调节血管张力外，EETs还可调节多种信号级联反应，并影响细胞增殖、细胞迁移和血管生成。受EETs调节的信号分子包括酪氨酸激酶和磷酸酶、丝裂原活化蛋白激酶、蛋白激酶A（PKA）、环氧化酶（COX）-2以及多种转录因子。本综述总结了CYP衍生的EETs在细胞信号传导中的作用，尤其关注它们作为内皮细胞超极化的细胞内放大器以及在细胞增殖和血管生成中的作用。CYP环氧化酶和CYP衍生的EETs的血管生成特性表明，这些酶很可能是抗血管生成和血管生成治疗的可及靶点。
